This invention relates to actively antimicrobial surfaces useful in avoiding, preventing and treating bacterial, fungal and microbial infections generally by releasing substances which are active in suppressing such organisms.
It has been appreciated for some time that certain ions and compounds are very effective antimicrobials for treating and/or killing bacterial and fungal entities. Metallic silver and silver salts have been used to inhibit growth of microorganisms on fresh wounds and the like. Silver nitrates have been commonly used as bacteriocidal agents.
A problem with the in vivo use of metal for metal ion therapy in preventing and treating infections is that the results have never been too spectacular. This is primarily due to the very low concentration of active metal ions and, in most situations, the rapid decline in the presence of metal ions when derived from salt solutions as administered to the infected area.
Considerable research work has been conducted in the field of silver metal treatment of bacterial infections. A variety of silver coated nylon cloths and fibers have been investigated, such as disclosed in Deitch et al. (March 1983), xe2x80x9cSilver-Nylonxe2x80x9d a New Antimicrobial Agent,xe2x80x9d Antimicrobial Agents and Chemotherapy, pp. 356-359; Mackeen et al. (January 1987), xe2x80x9cSilver-Coated Nylon Fiber as an Antibacterial Agent,xe2x80x9d Antimicrobial Agents and Chemotherapy, pp. 93-99; Deitch et al. (1987), xe2x80x9cSilver Nylon Cloth: In vitro and in vivo Evaluation of Antimicrobial Activity,xe2x80x9d J. Trauma 27(3).
In the last noted reference, the use of a weak direct current to increase the rate of release of silver ions was investigated to determine the impact of the increased presence of silver ions. This aspect has been further investigated by several groups as reported in Berger et al. (February 1976), xe2x80x9cElectrically Generated Silver Ions: Quantitative Effects on Bacterial and Mammalian Cells,xe2x80x9d Antimicrobial Agents and Chemotherapy, pp. 357-358; Berger et al. (November 1976), xe2x80x9cAntifungal Properties of Electrically Generated Metallic Ions,xe2x80x9d Antimicrobial Agents and Chemotherapy, pp. 856-860; Colmano et al. (1980), xe2x80x9cActivation of Antibacterial Silver Coatings on Surgical Implants by Direct Current: Preliminary Studies in Rabbits,xe2x80x9d Am. J. Vet. Res. 41(6):964-966; Falcone et al. (March 1986), xe2x80x9cInhibitory Effects of Electrically Activated Silver Material on Cutaneous Wound Bacteria,xe2x80x9d Plastic and Reconstructive Surgery, 77(3):455-459.
The technique of applying a current to a silver coated dressing or purifying devices or medical devices are also disclosed in U.S. Pat. Nos. 4,291,125; 4,411,648 and published U.K. Patent Application 2,189,677. It is thus apparent that considerable work has been conducted in the field of supplying silver ions in the area of infection or microbial contamination to control and eliminate microbial growth. This concept has been extrapolated further into the field of water treatment, such as disclosed in U.S. Pat. No. 4,407,865 where sand or diatomaceous earth is coated with metallic silver to provide a sterilizing effect as the contaminated waters flow over the filtered material.
It is apparent that sources of silver ions for instance would be particularly useful in surgical and other types of wound dressings. This aspect has been investigated and reported in U.S. Pat. No. 3,800,792, Canadian Patent 1,212,879 and published U.K. Patent Application 2,134,791. Metallic silver is incorporated into the dressing in one form or another and through dissolution silver ions arc released into the treated area. U.K. Patent Application 2,134,791 discloses that composites containing various metals, such as silver, gold, palladium, platinum and tin are useful in surgical dressings, where the preferred metal is silver. It is postulated that the slow release of silver ions is facilitated by a galvanic interaction with the moss; i.e., substrate, of the dressing with added metallic or nonmetallic compounds. However, this patent is silent on how galvanic interaction is developed and directed toward slow release of silver ions in this moss based dressing composition.
European Patent Application 0206024 discloses use of very smooth coatings of various metal combinations on medical devices, such as catheters to provide some antimicrobial activity when the devices are in contact with body fluids.
U.S. Pat. No. 4,418,686 and published U.K. Patent Application 2,194,155A are directed to an implant active in releasing silver ions to treat a bacterial infection. In U.S. Pat. No. 4,418,686, the implant consists of a plurality of spaced-apart metallic bands on a plastic insert where the surfaces of the bands consist of alternate materials, such as silver and gold. The presence of the silver and gold metals in the presence of body fluids results in a galvanic action which is intended to release or liberate silver ions. The implant is of a coiled construction and has metallic bands of considerable size. Such obtained macroscopic galvanic action is not effective, or suitable for most surgical dressings. U.S. Pat. No. 4,252,525 discloses a dental implant where spaced-apart bands of silver and gold are vacuum deposited onto the body of the implant. In addition to these metals, other suitable substances include aluminum, copper, zinc, alloys such as silver-zinc-allantoinate, and silver sufadiazine, for release of metal ions in providing bactericidal and germicidal action. Other types of implants, which have been treated with silver ions, include catheters which are marketed by Baxter Travenol Laboratories under the trade mark AgX.
The prior techniques involving the use of metal ions in treating microbial infections do not provide a sustained enhanced release of antimicrobial substances. Most existing devices are for short-term applications or suffer from the drawback of very slow release of material. The elements of interest are in fact among the most stable elements. They do not readily dissolve at significant rates on their own, and when in contact with most other metals, will cause such others preferential release. Even when in contact with nobler metals, the differences on the electrochemical scale are quite small that galvanic action occurring over macroscopic areas of contact does not significantly enhance the release of ions to the level needed.
It is appreciated that the release of metal ions may be expedited by the application of external electric current. However, in many applications, such as in normal bandages or implants, this is practically impossible.
A variety of materials are used every day in treating or preventing infections in humans, animals and the like. For example, catheters, sutures surgical gloves, implants, bandages, diapers, diaper liners, dressings, small adhesive dressings, sanitary napkins and insoles are just a few. Normally, bandages are used as a barrier to airborne pathogenic organisms infecting a cut or wound. However, once infection occurs, the bandage is no longer of any benefit. If the bandage were provided with a broad spectrum antimicrobial agent, on the portion of the bandage which is in contact with the wound and surrounding skin, the bandage becomes an actively rather than a passively antimicrobial surface or microbial barrier. Catheters, implants, bandages, dressings and other materials, such as above, are used extensively every day by millions of people. As a result, any form of antimicrobial material incorporated into these types of devices must be safe for general unsupervised use, should avoid selection of resistant strains, and should be cost effective. Furthermore, the materials may have to retain their flexibility such as with bandages so as to be readily usable.
It is an object of this disclosure to meet the difficulties encountered in the prior art and to make available both safe and economical actively antimicrobial surface structures and their method of manufacture.
Catheters, implants, bandages,diapers, diaper liners, dressings, and the like can be readily coated with thin films of active elements which, when in contact with body fluids, release substances and ions which stop the growth of or kill various types of microorganisms. As here described, there is no requirement to apply any outside electric current to maintain sustained levels of ion release to treat the infected area.
In accordance with a first aspect of the invention there is provided on a substrate for use with biological fluids, an actively antimicrobial surface film, comprising:
at least a pair of superimposed layers on the substrate, the layers of each pair being in electrical contact with each other, one of the layers in each pair being formed from a first element, the other of the layers in each pair being formed from a second element different from the first element, the second element being electrochemically nobler than the first element, at least the first element being an antimicrobial active metal element, each of the layers not in contact with the substrate being substantially discontinuous such that the layer below is exposed, whereby the first element releases ions of the antimicrobial active metal element when a biological fluid is brought into contact with the actively antimicrobial surface film.
In accordance with a second aspect of the invention there is provided a process for the production of an actively antimicrobial surface film on a substrate for use with electrolytes containing biological fluids, which comprises the steps of;
forming a first layer comprising one of a first element or a second element on a surface of the substrate;
forming a second layer comprising the other of the first element or the second element on the first layer; and texturing at least the second layer, and optionally the first layer to expose the first layer;
wherein at least the first element is an antimicrobial active metal element, the second element being different from, and electrochemically nobler than the first element, and the first and second elements in the first and second layers being in electrical contact with each other, and
whereby when a biological fluid is brought into contact with the actively antimicrobial surface film, both the first and second layers are contacted and the first element releases ions of the antimicrobial active metal element.
In accordance with a third aspect of the invention there is provided on a substrate for use in a biologically dynamic environment, an actively antimicrobial surface characterized in,
an alloy of elements, one of said elements being antimicrobially active and another of said elements being nobler in the electrochemical series than said one element, both said elements being mutually insoluble in solid solution in said alloy, said alloy thereby releasing ions of said one element when said surface is contacted by electrolyte containing biological fluid.
In accordance with a fourth aspect of the invention there is provided a process for the production of an actively antimicrobial surface film on a substrate for use in a biological environment, which comprises the steps of,
forming a first layer comprising a first element on a surface of said substrate;
texturing said first layer,
shadow depositing a second element on the said first layer to provide areas of said first layer covered by said second element and areas not covered by said second element,
at least one of the first and second elements being antimicrobially active and the other element being electrochemically nobler than said one element, said one element being ionically soluble in electrolytic biological fluid brought into contact with said layer.
A variety of ions are active in treating various types of microbial infections or acting as antimicrobials. Some preferred active element ions which have antimicrobial activity are those of platinum, gold, silver, copper, zinc, tin, antimony, and bismuth.
The antimicrobial films here described provide, in the presence of an electrolyte, such as provided by body or other biological fluid, an unexpected high reactivity of both the active element and the more noble element, which are released as ions (including ions of the nobler element in some instances, not merely in atomic form) to provide high antimicrobial efficacy.
All the mechanisms of ion release from the films are not yet fully understood, but it is thought that the large surface for galvanic action results, in the presence of electrolyte, in the high reactivity of the substances which are obtained.
Both micro-galvanic action and non-galvanic action will contribute to substance release from the film. The element or metal released by galvanic action, namely the one that is less noble on the electrochemical scale, is referred to herein as the xe2x80x9cactive element.xe2x80x9d Both the active element and the nobler element are released and contribute to the antimicrobial activity. The enhanced release of the nobler substances or ions from the actively antimicrobial surface film is referred to herein as occurring by xe2x80x9cnon-galvanic action.xe2x80x9d
Various embodiments of the invention are exemplified. Although discrete thin layers of the appropriate active elements or metals and more noble elements may be used, it is also evident that alloys of the various active elements with the nobler elements also work well. The alloy can be of one active element with one nobler element or an alloy of several elements, compounds or metals with at least one or more nobler element.
Alloys where the active element is insoluble in the solid state and where the other substances or element or elements behave more nobly in the electrochemical sense to the active element can be formed as a single layer actively antimicrobial surface, because the active element can be brought into solution through galvanic action of biological fluid directly on the alloy mass.
By building on the substrate a plurality of layers of a selected active element or metal, in combination with layers of an element metal or alloy more noble in the electrochemical scale than the selective active element, galvanic action is produced in the presence of biological fluids causing release of ions of the active element. For example, silver may be used as the element for building a first layer and then the nobler gold or platinum may be used for the adjacent layer, etc. The preferred nobler elements are selected from the group consisting of platinum, osmium, iridium, palladium, gold, silver and carbon. Since the layers are in contact with one another, electrons readily flow between them, such that, when the layers are in contact with body or biological fluids which carry various salts, galvanic action is set up as miniature or microscopic galvanic cells to release silver ions. Excellent effects can be accomplished for example by using copper in combination with silver, copper in combination with a copper silver alloy, or copper in combination with gold or a silver copper alloy in combination with gold.
The selection of elements determines the ions to be released.
In one preferred embodiment, a thin film structure is realized that releases, for example, gold, silver and/or copper for broad spectrum antimicrobial protection. The remaining elements of the preferred active elements group recited earlier are also very effective.
As in the special case for single layer alloys, with the absence of solid solubility of at least one element of interest discussed above, the thin film morphologies here described for a nominal film surface area, produce a relatively very large, exposed area of contact between dissimilar elements. This results in an enhanced level of release of elements, due to the creation of plurality of microscopic cells through which enhanced ion release by galvanic action is achieved. The importance of the exposed area of contact of the layer materials in an actively antimicrobial surface film is emphasized since simply having adjacent layers of the appropriate elements with their interfaces buried below the surface, does not produce generally (except in the case of a single layer alloy) enhanced antimicrobial activity.
Thin or micro-layers of elements can be laid down on a substance by conventional sputtering vaporization, electrochemical multilayer deposition or sol gel techniques. Many of the various thin film deposition techniques, as described in the monograph, Bunshah, R. F. (1982), xe2x80x9cDeposition Technologies for Films and Coatings,xe2x80x9d, Noves Publications, can be used to fabricate specifically metallic multilayer films. These include electrochemical and vacuum deposition methods. In the former, the required structures can be realized either by alternate deposition from two separate electrolytic baths, as described by L. M. Goldman, B. Blanpain and F. Spaepen (1986) J. Appl. Phys. 60:1374, or by pulsed electroplating from a single bath containing ions of the two metals of interest, as described in U.S. Pat. No. 4,652,348 to J. Yahalom and O. Zadok.
Among the vacuum techniques, the preferred processes are sputtering and evaporation, the latter using resistive, induction or electron-bema heating, since these are most suited to the high rate, large area deposition of metallic films of excellent quality. Multilayers can be realized in a batch process, appropriate for coating discrete substrates individually, wherein the article to be coated rotates or oscillates under two target sources of the elements of interest to be deposited that are shielded from one another so that the article alternately intercepts the vapor stream from one and then the other. Continuous multilayer coating can be realized in a coil to coil operation suitable for flexible substrates, by having the substrate web translate past an array of pairs or series of sources of the elements. Many such systems are in use, primarily for the deposition onto plastic of solar control films, comprising several layers of different materials, the plastic then being laminated to architectural glass. Metallic multilayer films, with individual layer thicknesses in the range of one to a few hundred nanometres (10 xc3x85 to 1000 xc3x85) have been the subject of much recent study due to the variety of interesting mechanical, electronic, and magnetic properties they exhibit for certain metal combinations, including noble metal couples of interest here, as tabulated in Chapter 2 by D. B. McWhan of the monograph xe2x80x9cSynthetic Modulated Structures,xe2x80x9d Chang and Giessen (eds.), Academic Press, 1985.
Similarly, ionic sputtering may be used to lay down single elements or a plurality (where two or more definite sources are used). The microlayers, as developed on the substrate, can have a thickness of a few molecules and hence be in the range of 5 to 500 nanometres in thickness. Preferred, however, is a total film thickness of about 1xcexc consisting, say, of ten layers each of about 1000 xc3x85 thick. The layers are deposited on the surface of the substrate which is to be in contact with the area to be treated; i.e., on a bandage, the layers are applied to the interior surface of the bandage such that when the bandage is applied, the flexible layered film is in contact directly with the body fluids. Since the film is porous the absorbent qualities of the underlying substrate are retained. The substrate need not be flexible however and film may also be deposited on rigid surfaces, such as catheters and implants.
A textured or open film composition can be created in a variety of ways. In a preferred embodiment, where the substrate itself has a rough surface, for example a latex, the layers may be deposited by direct sputtering; that is, substantially at 90xc2x0 to the surface. Since portions of the rough surface are, in effect, at an oblique angle to the sputtering beam, irregularities in the deposited surface are created.
When a smooth substrate is used, oblique angle sputtering of the microlayers will result in a suitable textured surface.
Surface structures produced by metal sputtering on rough surfaces and by oblique angle sputtering are described in Leamy (1980), xe2x80x9cThe Microstructure of Vapor Deposited Thin Layers,xe2x80x9d in Current Topics in Materials Science 6:311-434, and in Guenther (1984), xe2x80x9cMicrostructure of Vapor Deposited Optical Coatings,xe2x80x9d Appl. Opt. 23(21):3806-3816.
These references disclose that surfaces so produced have irregularities which give rise to nodules which grow within the metal laminates. Multiple layers thus become exposed at the surface at these nodules. This multiple exposure of metal interfaces provides for high reactivity of the layered textured film compositions and high antimicrobial efficacy.
Texturing may also be created by etching after deposition of the appropriate multilayers of the film.
The texturing of the surface to form a multitude of exposed microlayer interfaces can be generated by a variety of techniques. These include ion beam etching, back sputter etching, chemical etching and mechanical treatment, including, micro abrading, surface cracking by bending, flexing, ultrasonic treatment, expansion of the substrate surface such as by xe2x80x9cballooningxe2x80x9d of the article concerned, etc. One preferred method, which produces features on the submicron scale needed, yields uniform texture over large areas, and can be precisely controlled is argon ion beam etching. The development of pronounced texture on materials subjected to ion beam bombardment has been studied extensively, as described in the review article by Auciello, O. (1982) J. Vac. Sci. Tech. 19:841. Different textures are observed on different materials and these depend also on the parameters of the ion bema used. The mechanism for the induced texture is based on microscopic inhomogeneities, either chemical or microstructural, that are present in the material being etched. As the surface is eroded by sputtering under the action of the ion beam, such regions that may have lower sputtering yield than the surrounding matrix, act as a mask which causes the area around them to recede at a relatively higher rate. Once this localized preferential erosion is initiated, the resulting non-eroded structures act further to shadow the surrounding regions and so the texture becomes more accentuated as sputtering continues. The argon ions may be supplied from a glow discharge plasma created above the item being etched, which is biased electrically negative so that the positive argon ions are accelerated to it. Alternatively, the argon ions may be generated by broad beam ion sources which have recently become available commercially. The inhomogeneities in the material to be textured can be intrinsic such as impurities and defects. Impurities may also be supplied externally during etching as in the known process of seeded texturing wherein a particular seed material, such as tantalum, is ion deposited at a low rate onto the specimen simultaneously with the sputter etching of the specimen by the ion beam. In the thin film to be etched, an inhomogeneous microstructure can be created in the material during deposition providing both chemical and microstructural modulation. The resulting texture and composition of the etched film is then, in general, dependent on the particular materials in combination and the structure of the layers. Specific textures have been found in such sputtered multilayer films of Ag and Cu as described by Tanemura, M. and Okuyama, F. (1986) J. Vac. Sci. Tech. A4 4(5):2369-2372. These were studied by them in conjunction with the difficulties that arise from the induced texture in analysing the multilayer films with ion-based spectroscopic techniques. No consideration, however, was given to potential uses of the texture for its own sake.
Specific embodiments of the invention will now be described with reference to the accompanying drawings.